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CC BY 4.0 · Rev Bras Ginecol Obstet 2019; 41(12): 710-717
DOI: 10.1055/s-0039-3400457
Original Article
Thieme Revinter Publicações Ltda Rio de Janeiro, Brazil

Association of Menopausal Status, Expression of Progesterone Receptor and Ki67 to the Clinical Response to Neoadjuvant Chemotherapy in Luminal Breast Cancer

Associação de status menopausal, expressão de receptor de progesterona e de Ki67 à resposta clínica à quimioterapia neoadjuvante no câncer luminal de mama
Leonardo Roberto da Silva
1   Universidade Estadual de Campinas, Campinas, SP, Brazil
,
Renato Flora Vargas
1   Universidade Estadual de Campinas, Campinas, SP, Brazil
,
Júlia Yoriko Shinzato
1   Universidade Estadual de Campinas, Campinas, SP, Brazil
,
Sophie Françoise Mauricette Derchain
1   Universidade Estadual de Campinas, Campinas, SP, Brazil
,
Susana Ramalho
1   Universidade Estadual de Campinas, Campinas, SP, Brazil
,
Luiz Carlos Zeferino 
1   Universidade Estadual de Campinas, Campinas, SP, Brazil
› Author Affiliations
Further Information

Publication History

15 July 2019

09 October 2019

Publication Date:
19 December 2019 (online)

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Abstract

Objective To identify the biomarkers of response to neoadjuvant chemotherapy in early luminal breast cancer.

Methods A cross-sectional study that included all patients with early or locally-advanced luminal breast cancer submitted to neoadjuvant chemotherapy between 2013 and 2014. Demographic, clinic and pathologic data were retrieved from patient records. The expressions of the estrogen receptor (ER), the progesterone receptor (PR), and Ki67 were analyzed by immunohistochemistry (IHC). The status of the human epidermal growth factor receptor 2 (HER2) was evaluated by IHC and fluorescent in situ hybridization (FISH). Independent predictors of clinic and pathologic response were evaluated by stepwise logistic regression models and receiver operating characteristic (ROC) curve analysis.

Results Out of 298 patients identified, 115 were included in the analysis. Clinical complete response (cCR) was observed in 43.4% of the patients (49/113), and pathologic complete response (pCR) was observed in 7.1% (8/115) of the patients. The independent predictors of cCR were premenopausal status (p < 0.001), low PR expression (≤ 50% versus > 50%; p = 0.048), and Ki67 expression ≥ 14% (versus < 14%; p = 0.01). Patients with cCR were more commonly submitted to breast conserving surgery (34.7% versus 7.8%; p < 0.001). Increasing cut-off points for Ki67 expression were associated with an increase in specificity and a decrease in sensitivity to identify patients with cCR.

Conclusion Premenopausal status, lower PR expression and higher Ki67 expression were associated with a higher rate of cCR to neoadjuvant chemotherapy in luminal breast cancer.

Resumo

Objetivo Identificar biomarcadores de resposta à quimioterapia neoadjuvante em câncer luminal de mama.

Métodos Estudo transversal em que foram incluídas todas as pacientes com câncer luminal de mama em estádio inicial ou localmente avançado que foram submetidas a quimioterapia neoadjuvante nos anos de 2013 e 2014. Dados demográficos, clínicos e patológicos foram obtidos de prontuários médicos. As expressões de receptor de estrogênio (RE), de receptor de progesterona (RP), e de Ki67 foram avaliadas por imuno-histoquímica (IHQ). A expressão do receptor tipo 2 do fator de crescimento epidérmico humano (human epidermal growth factor receptor 2, HER2) foi avaliada por IHQ e hibridização in situ por imunofluorescência (HISI). Análises de regressão logística e de curva de característica de operação do receptor (COR) foram usadas para investigar fatores preditivos independentes de resposta clínica e patológica.

Resultados De 298 pacientes identificadas, 115 foram incluídas na análise. Resposta clínica completa (RCc) foi observada em 43.4% das pacientes (49/113), e resposta patológica completa (RPc), em 7.1% (8/115). Os fatores preditivos independentes de RCc foram status menopausal (p < 0.001), baixa expressão de RP (≤ 50% versus > 50%; p = 0.048), e expressão de Ki67 ≥ 14% (versus < 14%; p = 0.01). Pacientes com RCc apresentaram maior probabilidade de serem submetidas a cirurgia conservadora da mama (34.7% versus 7.8%; p < 0.001). Aumento no ponto de corte para expressão de Ki67 foi associado a aumento da especificidade e redução da sensibilidade na identificação de pacientes com RCc.

Conclusão Status premenopausal, baixa expressão de RP e maior expressão de Ki67 estiveram associados a maior taxa de RCc à quimioterapia neoadjuvante no câncer luminal de mama.

Keywords

antineoplastic agents - breast neoplasms - segmental mastectomy - neoadjuvant therapy - estrogen receptors

Palavras-chave

agentes antineoplásicos - neoplasias da mama - mastectomia segmentar - terapia neoadjuvante - receptores estrogênicos

Contributions

1. Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work: Leonardo Roberto da Silva, Renato Flora Vargas, Júlia Yoriko Shinzato, Sophie Françoise Mauricette Derchain, Susana Ramalho, Luiz Carlos Zeferino.


2. Draft of the work or critical revision critically regarding important intellectual content: Leonardo Roberto da Silva, Renato Flora Vargas, Júlia Yoriko Shinzato, Sophie Françoise Mauricette Derchain, Susana Ramalho, Luiz Carlos Zeferino.


3. Final approval of the version to be published: Leonardo Roberto da Silva, Renato Flora Vargas, Júlia Yoriko Shinzato, Sophie Françoise Mauricette Derchain, Susana Ramalho, Luiz Carlos Zeferino.


 

  • References

  • 1 Perou CM, Sørlie T, Eisen MB. , et al. Molecular portraits of human breast tumours. Nature 2000; 406 (6797): 747-752 . Doi: 10.1038/35021093
    CrossrefPubMedGoogle Scholar
  • 2 Sørlie T, Perou CM, Tibshirani R. , et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001; 98 (19) 10869-10874 . Doi: 10.1073/pnas.191367098
    CrossrefPubMedGoogle Scholar
  • 3 Weigelt B, Reis-Filho JS. Molecular profiling currently offers no more than tumour morphology and basic immunohistochemistry. Breast Cancer Res 2010; 12 (Suppl. 04) S5 . Doi: 10.1186/bcr2734
    CrossrefPubMedGoogle Scholar
  • 4 Banin Hirata BK, Oda JM, Losi Guembarovski R, Ariza CB, de Oliveira CE, Watanabe MA. Molecular markers for breast cancer: prediction on tumor behavior. Dis Markers 2014; 2014: 513158 . Doi: 10.1155/2014/513158
    CrossrefPubMedGoogle Scholar
  • 5 Carey LA, Winer EP. Defining success in neoadjuvant breast cancer trials. Lancet 2014; 384 (9938): 115-116 . Doi: 10.1016/S0140-6736(14)60034-9
    CrossrefPubMedGoogle Scholar
  • 6 von Minckwitz G, Untch M, Blohmer JU. , et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 2012; 30 (15) 1796-1804 . Doi: 10.1200/JCO.2011.38.8595
    CrossrefPubMedGoogle Scholar
  • 7 Fasching PA, Heusinger K, Haeberle L. , et al. Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment. BMC Cancer 2011; 11: 486 . Doi: 10.1186/1471-2407-11-486
    CrossrefPubMedGoogle Scholar
  • 8 Colleoni M, Viale G, Zahrieh D. , et al. Chemotherapy is more effective in patients with breast cancer not expressing steroid hormone receptors: a study of preoperative treatment. Clin Cancer Res 2004; 10 (19) 6622-6628 . Doi: 10.1158/1078-0432.CCR-04-0380
    CrossrefPubMedGoogle Scholar
  • 9 Yerushalmi R, Woods R, Ravdin PM, Hayes MM, Gelmon KA. Ki67 in breast cancer: prognostic and predictive potential. Lancet Oncol 2010; 11 (02) 174-183 . Doi: 10.1016/S1470-2045(09)70262-1
    CrossrefPubMedGoogle Scholar
  • 10 Sueta A, Yamamoto Y, Hayashi M. , et al. Clinical significance of pretherapeutic Ki67 as a predictive parameter for response to neoadjuvant chemotherapy in breast cancer: is it equally useful across tumor subtypes?. Surgery 2014; 155 (05) 927-935 . Doi: 10.1016/j.surg.2014.01.009
    CrossrefPubMedGoogle Scholar
  • 11 Horimoto Y, Arakawa A, Tanabe M. , et al. Ki67 expression and the effect of neo-adjuvant chemotherapy on luminal HER2-negative breast cancer. BMC Cancer 2014; 14: 550 . Doi: 10.1186/1471-2407-14-550
    CrossrefPubMedGoogle Scholar
  • 12 Tavassoeli FA, Devilee P. Pathology and Genetics of Tumors of the Breast and Female Genital Organs. 3rd ed. Lyon: IARC; 2003
    Google Scholar
  • 13 Singletary SE, Allred C, Ashley P. , et al. Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol 2002; 20 (17) 3628-3636 . Doi: 10.1200/JCO.2002.02.026
    CrossrefPubMedGoogle Scholar
  • 14 Mazouni C, Peintinger F, Wan-Kau S. , et al. Residual ductal carcinoma in situ in patients with complete eradication of invasive breast cancer after neoadjuvant chemotherapy does not adversely affect patient outcome. J Clin Oncol 2007; 25 (19) 2650-2655 . Doi: 10.1200/JCO.2006.08.2271
    CrossrefPubMedGoogle Scholar
  • 15 Hammond MEH, Hayes DF, Dowsett M. , et al. American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 2010; 28 (16) 2784-2795 . Doi: 10.1200/JCO.2009.25.6529
    CrossrefPubMedGoogle Scholar
  • 16 Dowsett M, Nielsen TO, A'Hern R. , et al; International Ki-67 in Breast Cancer Working Group. Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst 2011; 103 (22) 1656-1664 . Doi: 10.1093/jnci/djr393
    CrossrefPubMedGoogle Scholar
  • 17 Wolff AC, Hammond MEH, Hicks DG. , et al; American Society of Clinical Oncology; College of American Pathologists. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 2013; 31 (31) 3997-4013 . Doi: 10.1200/JCO.2013.50.9984
    CrossrefPubMedGoogle Scholar
  • 18 Boughey JC, McCall LM, Ballman KV. , et al. Tumor biology correlates with rates of breast-conserving surgery and pathologic complete response after neoadjuvant chemotherapy for breast cancer: findings from the ACOSOG Z1071 (Alliance) Prospective Multicenter Clinical Trial. Ann Surg 2014; 260 (04) 608-614 , discussion 614–616. Doi: 10.1097/SLA.0000000000000924
    CrossrefPubMedGoogle Scholar
  • 19 Fiorentino C, Berruti A, Bottini A. , et al. Accuracy of mammography and echography versus clinical palpation in the assessment of response to primary chemotherapy in breast cancer patients with operable disease. Breast Cancer Res Treat 2001; 69 (02) 143-151
    CrossrefPubMedGoogle Scholar
  • 20 Shin HJ, Kim HH, Ahn JH. , et al. Comparison of mammography, sonography, MRI and clinical examination in patients with locally advanced or inflammatory breast cancer who underwent neoadjuvant chemotherapy. Br J Radiol 2011; 84 (1003): 612-620 . Doi: 10.1259/bjr/74430952
    CrossrefPubMedGoogle Scholar
  • 21 Rastogi P, Anderson SJ, Bear HD. , et al. Preoperative chemotherapy: updates of national surgical adjuvant breast and bowel project protocols B-18 and B-27. J Clin Oncol 2008; 26 (05) 778-785 . Doi: 10.1200/JCO.2007.15.0235
    CrossrefPubMedGoogle Scholar
  • 22 Evans TRJ, Yellowlees A, Foster E. , et al. Phase III randomized trial of doxorubicin and docetaxel versus doxorubicin and cyclophosphamide as primary medical therapy in women with breast cancer: an anglo-celtic cooperative oncology group study. J Clin Oncol 2005; 23 (13) 2988-2995 . Doi: 10.1200/JCO.2005.06.156
    CrossrefPubMedGoogle Scholar
  • 23 Gnerlich JL, Deshpande AD, Jeffe DB, Sweet A, White N, Margenthaler JA. Elevated breast cancer mortality in women younger than age 40 years compared with older women is attributed to poorer survival in early-stage disease. J Am Coll Surg 2009; 208 (03) 341-347 . Doi: 10.1016/j.jamcollsurg.2008.12.001
    CrossrefPubMedGoogle Scholar
  • 24 Fredholm H, Eaker S, Frisell J, Holmberg L, Fredriksson I, Lindman H. Breast cancer in young women: poor survival despite intensive treatment. PLoS One 2009; 4 (11) e7695 . Doi: 10.1371/journal.pone.0007695
    CrossrefPubMedGoogle Scholar
  • 25 Copson E, Eccles B, Maishman T. , et al; POSH Study Steering Group. Prospective observational study of breast cancer treatment outcomes for UK women aged 18-40 years at diagnosis: the POSH study. J Natl Cancer Inst 2013; 105 (13) 978-988 . Doi: 10.1093/jnci/djt134
    CrossrefPubMedGoogle Scholar
  • 26 Collins LC, Marotti JD, Gelber S. , et al. Pathologic features and molecular phenotype by patient age in a large cohort of young women with breast cancer. Breast Cancer Res Treat 2012; 131 (03) 1061-1066 . Doi: 10.1007/s10549-011-1872-9
    CrossrefPubMedGoogle Scholar
  • 27 Azim Jr HA, Michiels S, Bedard PL. , et al. Elucidating prognosis and biology of breast cancer arising in young women using gene expression profiling. Clin Cancer Res 2012; 18 (05) 1341-1351 . Doi: 10.1158/1078-0432.CCR-11-2599
    CrossrefPubMedGoogle Scholar
  • 28 Li X, Zhang R, Liu Z, Li S, Xu H. The genetic variants in the PTEN/PI3K/AKT pathway predict susceptibility and CE(A)F chemotherapy response to breast cancer and clinical outcomes. Oncotarget 2017; 8 (12) 20252-20265 . Doi: 10.18632/oncotarget.15690
    CrossrefPubMedGoogle Scholar
  • 29 Deng L, Chen J, Zhong XR. , et al. Correlation between activation of PI3K/AKT/mTOR pathway and prognosis of breast cancer in Chinese women. PLoS One 2015; 10 (03) e0120511 . Doi: 10.1371/journal.pone.0120511
    CrossrefPubMedGoogle Scholar
  • 30 Ravdin PM, Green S, Dorr TM. , et al. Prognostic significance of progesterone receptor levels in estrogen receptor-positive patients with metastatic breast cancer treated with tamoxifen: results of a prospective Southwest Oncology Group study. J Clin Oncol 1992; 10 (08) 1284-1291 . Doi: 10.1200/JCO.1992.10.8.1284
    CrossrefPubMedGoogle Scholar
  • 31 Bardou VJ, Arpino G, Elledge RM, Osborne CK, Clark GM. Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases. J Clin Oncol 2003; 21 (10) 1973-1979 . Doi: 10.1200/JCO.2003.09.099
    CrossrefPubMedGoogle Scholar
  • 32 Yamamoto Y, Yamamoto-Ibusuki M, Iwase H. Menopausal status should be taken into consideration for patients with luminal a breast cancer in terms of the effect of differential biology on prognosis. J Clin Oncol 2013; 31 (19) 2516 . Doi: 10.1200/JCO.2013.49.4062
    CrossrefPubMedGoogle Scholar
  • 33 Creighton CJ, Kent Osborne C, van de Vijver MJ. , et al. Molecular profiles of progesterone receptor loss in human breast tumors. Breast Cancer Res Treat 2009; 114 (02) 287-299 . Doi: 10.1007/s10549-008-0017-2
    CrossrefPubMedGoogle Scholar
  • 34 Tokunaga E, Kataoka A, Kimura Y. , et al. The association between Akt activation and resistance to hormone therapy in metastatic breast cancer. Eur J Cancer 2006; 42 (05) 629-635 . Doi: 10.1016/j.ejca.2005.11.025
    CrossrefPubMedGoogle Scholar
  • 35 Xu L, Liu YH, Ye JM. , et al. [Relationship between Ki67 expression and tumor response to neoadjuvant chemotherapy with anthracyclines plus taxanes in breast cancer]. Zhonghua Wai Ke Za Zhi 2010; 48 (06) 450-453 . Doi: 10.3760/cma.j.issn.0529-5815.2010.06.015
    PubMedGoogle Scholar
  • 36 Esposito A, Criscitiello C, Curigliano G. Highlights from the 14th St Gallen International Breast Cancer Conference 2015 in Vienna: dealing with classification, prognostication, and prediction refinement to personalize the treatment of patients with early breast cancer. Ecancer 2015; 9: 518 . Doi: 10.3332/ecancer.2015.518
    CrossrefPubMedGoogle Scholar
  • 37 Cortazar P, Zhang L, Untch M. , et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014; 384 (9938): 164-172 . Doi: 10.1016/S0140-6736(13)62422-8
    CrossrefPubMedGoogle Scholar
  • 38 Alba E, Lluch A, Ribelles N. , et al. High proliferation predicts pathological complete response to neoadjuvant chemotherapy in early breast cancer. Oncologist 2016; 21 (02) 150-155 . Doi: 10.1634/theoncologist.2015-0312
    CrossrefPubMedGoogle Scholar
  • 39 Carey LA, Dees EC, Sawyer L. , et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 2007; 13 (08) 2329-2334 . Doi: 10.1158/1078-0432.CCR-06-1109
    CrossrefPubMedGoogle Scholar